DESCRIPTION (provided by principal investigator): This application is the first resubmission of a competing renewal of the Seychelles Child Development and Nutrition Study (SCDNS), initially funded in 2000 to examine the hypothesis that maternal nutritional and dietary status during pregnancy might modify the toxicity of MeHg when exposure stems from consumption of a diet high in fish. During the initial period of the SCDNS, prenatal exposure to MeHg and selected nutrients were measured and neurodevelopment of cohort of 229 children was evaluated through the first 30 months of life. We found no evidence of independent adverse effects of prenatal MeHg on developmental outcomes within the range of MeHg exposure studied (1-18 ppm in maternal hair). However, there was an adverse effect of prenatal MeHg exposure on psychomotor ability when statistical models were adjusted for maternal dietary intake and nutritional status. This effect was due to maternal serum levels of )-3 and )-6 long-chain polyunsaturated fatty acids (LCPUFA). )-3 LCPUFA levels had a beneficial influence on psychomotor development while both MeHg and )-6 LCPUFA adversely affected psychomotor development. Thus, LCPUFA might have a direct impact on developmental endpoints and modify the MeHg effect. It is also likely that other nutritional covariates might further modify the toxicity of MeHg. Our aim is to extend the SCDNS to pursue an innovate study to test in more depth the parameters of our recently published novel finding showing an apparent modulation of MeHg neurotoxicity by LCPUFA. The initial study measured a limited number of candidate nutrients present in fish and enrolled a cohort based on power estimates from our earlier studies. In retrospect, we underestimated the complexity of nutrient effects on neurotoxicity and development. Using a larger more powerful cohort (n~1,500) being recruited by the Seychelles Ministry of Health, we plan to confirm the main effects found to date and test interactions between MeHg and LCPUFA. Our plan also includes assaying vitamin E and selenium status in pregnancy as possible modifiers of the combined effects of MeHg and LCPUFA on development. The new cohort will be assessed for development using measures that showed an association between either MeHg alone, LCPUFA alone or the combination of both in our initial study. Measures of social communication and behavior will be added to increase the scope of the assessment Continuing the SCDNS utilizing a larger cohort and focusing specifically on the role of LCPUFA in relation to MeHg neurotoxic exposures and child development should allow us to efficiently pursue the scientific questions raised by our first five years of study. It will also contribute to establishing the risks and benefits of fish consumption during pregnancy. In addition we will begin to study the broader question of how diet may interact with MeHg exposure. These results should enable regulators to promulgate scientifically based advisories concerning safety of consuming fish during pregnancy.